tbuckley/cabot-search huggingface dataset:
Ex ante budget impact analysis (BIA) of PD-1 inhibitor toripalimab plus gemcitabine-cisplatin (T+GC) versus a simulated pembrolizumab regimen in first line (1L) treatment of recurrent or metastatic nasopharyngeal cancer (rmNPC).
Authors: Ivo Abraham, Robert B. Geller, Paul D. Walden, Karen MacDonald
Journal: Journal of Clinical Oncology (2022)

e18024 Background: Interim results of the JUPITER-02 randomized double-blind phase 3 trial demonstrated a PFS benefit for T+GC (11.7 m) vs placebo+GC (8m) in 1L treatment of rmNPC. The KEYNOTE-028 nonrandomized (single group assignment) phase 1b trial showed the potential benefit of pembrolizumab in previously treated NPC. The trials were not comparable in population and design, precluding a direct comparison. We performed an ex ante BIA comparing T+GC to a simulated pembrolizumab+GC (sP+GC) regimen under an assumed equivalence in efficacy and safety. Methods: An ex ante budget impact model (budget holder perspective; accrual approach) compared a treatment mix “without” T+GC (only sP+GC) to one “with” T+GC in an annual incident US population of 1200 patients (year 1), a 5y time horizon, and a fixed 50/50 market share split. Population adjustments were for discontinuation, death, and progression with corresponding medication adjustments to estimate fully treated patient equivalents. Cost inputs included: drugs (average sales price), drug administration, and grade 3/4 adverse event (AE) management. Three scenarios were modeled: toripalimab priced at 70%, 80% and 90% of pembrolizumab. Results: In the “without” scenario, the 5y costs of sP+GC treatment totaled $2,062,509,042 and the 5y cost of managing AEs $210,382,926, for a total of $2,272,891,967. In the “with” scenario at 50% market share, the corresponding 5y costs for sP+GC declined to $1,031,254,521 for treatment and $105,191,463 in AE costs, for a total of $1,136,445,984. The corresponding costs for T+GC priced at 70%, 80%, 90% of pembrolizumab were $746,834,887, $841,641,432 and $936,447,976 (treatment) and $105,191,463 (AE management), for 5y gross budget impacts of $852,026,350, $946,832,895 and $1,041,639,439. Net savings “with” T+GC were $49,331,430, $32,887,620 and $16,443,810 in 2022 rising to $64,974,264, $43,316,176 and $21,658,088 by 2026. The total 5y net budget impact of adding T+GC to the treatment mix totaled $284,419,634, $189,613,089 and $94,806,545 in savings. Conclusions: Citing the findings from the JUPITER-02 trial of T+GC, regimens including a PD-1 inhibitor, gemcitabine and cisplatin are now a NCCN category 2A recommendation for 1L treatment of rmNPC. This ex ante BIA demonstrates the substantial savings potential of toripalimab (at a discounted cost compared to pembrolizumab) in rmNPC. With forthcoming final JUPITER-02 data showing a PFS benefit of 21.4m, the value of an available, lower-priced and efficacious anti-PD1 agent is highly significant to patients, providers and payers in terms of both clinical efficacy and cost efficiency. Emerging data suggest that toripalimab may be effective in more frequently occurring tumor types and the savings from such expanded access are likely to be multifold.
Apatinib in recurrent or metastatic head and neck cancer patients.
Authors: Qiuji WU, Jia Liu, Shaojie Li, Juan Wang, Yahua Zhong
Journal: Journal of Clinical Oncology (2022)

e18010 Background: Apatinib is a small tyrosine kinase inhibitor targeting the vascular endogenous growth receptor 2 (VEGFR-2) that shows potent antitumor activities in various advanced cancers via the inhibition of neo-angiogenesis. The effect of apatinib in recurrent or metastatic head and neck cancers has not been fully demonstrated. Methods: Patients with recurrent or metastatic head and neck cancers consecutively treated in our institute by apatinib from January 2015 to December 2020 were enrolled. Daily 250 mg or 500 mg apatinib was given with or without chemotherapy according to patients' tolerance. A part of the patients also received palliative radiotherapy. Disease response, treatment-related toxicities and patient survival were analyzed. Toxicity was assessed by CTCAE v4.0. Kaplan-Meier analysis was used to estimate patients' overall survival. The R software (version 3.6.3) were used for statistical analysis. Results: A total of 73 patients were enrolled in this study. There were 59 males and 14 females with the median age of 55 (range: 27-80) years. Most patients had a performance status of 0 (15/73, 20.5%) and 1 (51/73, 69.9%). There were 29 oral cavity cancers, 20 nasopharyngeal carcinomas, 8 salivary gland cancers, 7 nasal and paranasal sinus cancers and 9 other malignancies. Pathologically, 47 were squamous cell carcinoma, 18 were adenoid cystic carcinoma, and the rest 8 were adenocarcinoma, sarcoma and melanoma. The majority of patients were with metastatic diseases (57/74, 78.1%). Nine of the 73 (12.3%) received apatinib as first-line treatment, 22 (30.1%) as second-line and 42 (57.5%) as more than second-line treatments. Forty patients received S-1 or capecitabine chemotherapy, 2 received nab-paclitaxel and 1 received gemcitabine. Ten patients received palliative radiotherapy. The most frequent toxicities were anemia (37/73, 50.7%), leucopenia (27/73, 37.0%), thrombocytopenia (20/73, 27.4%), proteinuria (20/73, 27.4%), arterial hypertension (17/73, 23.3%), hand-foot syndrome (17/73, 23.3%). Hemorrhage occurred in 10 (13.7%) patients. No treatment-associated death was noted. The median follow-up was 29.9 months. Fifty-six patients had evaluable tumor response. Complete response occurred in 1 patients. Partial response was seen in 3 patients. Most patients had stable disease (29/56, 51.8%) or progressive disease (23/56, 41.1%). By the end of the last follow-up, 33 patients died of disease progression. The median overall survival was 29.6 months. Conclusions: Apatinib showed modest antitumor activities in recurrent or metastatic head and neck cancers. The side effects were manageable. The effect of apatinib in recurrent or metastatic head and neck cancers warrants further studies in larger-scale randomized studies.
A phase 1 study of the novel immunotoxin MT-5111 in patients with HER2+ tumors: Interim results.
Authors: Brian Andrew Van Tine, Joleen M. Hubbard, Monica M. Mita, Minal A. Barve, Erika P. Hamilton, Andrew J. Brenner, Frances Valdes, Daniel H. Ahn, Jason S. Starr, Joshua Pelham, Thomas Strack, Amy Yuet, Diana Yurewicz, Taunya J. Smith, Andres Machado, William Jeffery Edenfield, Aki Morikawa, Meena Okera, Nihal E. Abdulla, Zev A. Wainberg
Journal: Journal of Clinical Oncology (2022)

2583 Background: MT-5111 is a 55kD engineered toxin body (ETB) targeting HER2 in solid tumors that binds to an epitope distinct from trastuzumab and pertuzumab, offering potential combination strategies with other HER2-targeting agents. MT-5111 may demonstrate efficacy in patients (pts) resistant to other HER2-targeting agents, as its mechanism of action induces direct cell kill via enzymatic and permanent ribosome destruction. Methods: This is a phase 1 study in adults with advanced HER2+ solid tumors. The dose-escalation portion (Part A) enrolls pts into sequential dose cohorts, followed by Part B expansion cohorts for HER2+ breast cancer (BC), gastroesophageal adenocarcinoma (GEA), and any other HER2+ cancer (CA). MT-5111 is dosed weekly IV over 30 min in each 21-day treatment (tx) cycle until disease progression, unacceptable toxicity, death or withdrawn consent. Results: As of Jan 2022, 27 pts had enrolled in Part A cohorts (0.5 to 10 µg/kg/dose) with completed DLT assessments: 9 (33%) pts were male and 18 (67%) female, median age 67 and a median of 4 prior systemic and 2 prior HER2-targeting tx. Common tissue types were BC (9/30%), biliary CA (6/22%), GEA (4/15%). The following safety data reflect 33 treated pts to date including ongoing 13 µg/kg/dose Part A and 10 µg/kg/dose BC expansion cohorts. No Grade (G) 4/5 tx-emergent adverse events (AEs) or DLTs occurred. Tx-related AEs occurred in 17 (52%) pts, most commonly G1/2 fatigue (8/24%). 3 pts had G1 troponin elevations without clinical signs or symptoms of cardiac distress: 1 at 6.75 µg/kg/dose, 2 at 10 µg/kg/dose. 2 pts (3 and 4.5 µg/kg/dose) had reversible G2 and G1, respectively, infusion-related reactions (IRR)s. A comparison of cytokines from baseline to on-treatment timepoints reveals no evidence of significant changes, even in pts with IRR. Best response per RECIST thus far was stable disease (SD) in 7 pts or non-CR/non-PD in 2 pts: 1 pt had SD for 12 weeks (wks) (4.5 μg/kg, pancreatic CA); 1 pt (1 μg/kg/dose, BC) had non-CR/non-PD for 30 wks; 1 pt (10 μg/kg/dose, GEA) has ongoing SD for 18 wks. AUC last data match PK simulations in non-human primate studies. C max at 10 µg/kg/dose is ≥5 times the IC 50 values of high HER2 expressing gastric CA and BC cell lines while approaching the IC 50 of a moderately HER2 expressing liver CA cell line. Conclusions: MT-5111 is well tolerated to-date with no clinically significant immuno/cardiotoxicity. Dose escalation is ongoing at a dose of 13µg/kg, expected to be required for efficacious exposure. Clinical trial information: NCT04029922.
Colon adjuvant chemotherapy based on evaluation of residual disease (CIRCULATE-US): NRG-GI008.
Authors: Arvind Dasari, Yan Lin, Scott Kopetz, Samuel A. Jacobs, Peter C. Lucas, Ibrahim Halil Sahin, Dustin A. Deming, Philip Agop Philip, Theodore S. Hong, Yesenia Rojas-Khalil, Norman Wolmark, Greg Yothers, Thomas J. George, Christopher Hanyoung Lieu
Journal: Journal of Clinical Oncology (2022)

TPS3643 Background: Currently, there are no biomarkers validated prospectively in randomized studies for resected colon cancer (CC) to determine need for adjuvant chemotherapy (AC). However, circulating tumor DNA (ctDNA) represents a highly specific and sensitive approach (especially with serial monitoring) for identifying minimal/molecular residual disease (MRD) post-surgery in CC patients (pts), and may outperform traditional clinical and pathological features in prognosticating risk for recurrence. CC pts who do not have detectable ctDNA (ctDNA-) are at a much lower risk of recurrence and may be spared the toxicities associated with AC. Furthermore, for CC pts with detectable ctDNA (ctDNA+) who are at a very high risk of recurrence, the optimal AC regimen has not been established. We hypothesize that for pts whose CC has been resected, ctDNA status may be used to risk stratify for making decisions about AC. Methods: In this prospective phase II/III trial, up to 1,912 pts with resected stage III A, B (all pts) and stage II, IIIC (ctDNA+ only) CC will be enrolled. Based on the post-operative ctDNA status using personalized and tumor informed assay (SignateraTM, bespoke assay), those who are ctDNA- (Cohort A) will be randomized to immediate AC with fluoropyrimidine (FP) + oxaliplatin (Ox) for 3-6 mos per established guidelines vs . serial ctDNA monitoring. Patients who are ctDNA+ post-operatively or with serial monitoring (Cohort B) will be randomized to FP+Ox vs . more intensive AC with addition of irinotecan (I) for 6 mos. The primary endpoints for Cohort A are time to ctDNA+ status (phase II) and disease-free survival (DFS) in phase III in the immediate vs . delayed AC arms. The primary endpoint for Cohort B is DFS in the FP+Ox vs FP+Ox+I arms for both phase II and phase III portions of the trial. Secondary endpoints include prevalence of detectable ctDNA post-operatively, time-to-event outcomes (overall survival and time to recurrence) by ctDNA status, and the assessment of compliance to adjuvant therapy. Biospecimens including archival tumor tissue, post-operative and serial matched/normal blood samples will be collected for exploratory correlative research. Active enrollment across the NCTN started in early 2022. Support: U10-CA-180868, -180822; UG1CA-189867; Clinical trial information: NCT05174169.
A tool to predict survival outcomes and guide adjuvant immunotherapy recommendations for patients with stage II melanoma.
Authors: Alexander Varey, Georgina V. Long, Richard A. Scolyer, Jeffrey E. Gershenwald, Julie Simon, John F. Thompson, Serigne N. Lo
Journal: Journal of Clinical Oncology (2022)

e21556 Background: Patients diagnosed with AJCC stage II melanoma have a 10-year melanoma specific survival (MSS) of 84%, ranging from 88% for stage IIA to 75% for stage IIC. The 12%-25% rate of melanoma mortality correlates with the rate of recurrence for these patients. Current prognostic tools are based on the AJCC 8 th Edition (AJCC-8), which gives MSS based on tumor thickness and ulceration status but does not consider any other patient or tumor characteristics. The rate of recurrence-free survival (RFS) may be more important than MSS in deciding whether a patient should be offered adjuvant immunotherapy. We have therefore developed a risk prediction tool to assist in this process. Methods: Data were extracted from a large Australian melanoma treatment center research database for patients diagnosed with stage II melanoma (n = 3243). Parameters included: age, sex, tumor thickness, mitotic rate, ulceration status, lymphovascular invasion, presence of tumor infiltrating lymphocytes, regression, sentinel node status, presence of satellites, body site, recurrence (including time to event) and date of last follow-up. Multivariable Cox regression analyses were performed to develop models for survival prediction. These were then externally validated using a dataset from a large US melanoma treatment center (n = 703). Discrimination and calibration of each model were assessed using the C-statistics and calibration plots respectively. Results: The table shows the C-statistics for the Australian RFS model and the AJCC-8 staging, along with validations. These demonstrated statistically significant discrimination gains by using the Australian model over the AJCC model, which ranged from 8.3% to 12.2%. The Australian model was well calibrated. Conclusions: There was good discrimination of the RFS model for individual patients over both 5 and 10 years, which held true on external validation. This model offers considerable improvement in discriminative accuracy for predicting RFS compared to using the AJCC-8 staging and therefore may be clinically useful to guide adjuvant immunotherapy recommendations. An online tool will be made available at www.melanomarisk.org.au.[Table: see text]
Assessing effectiveness of first-line carboplatin, pemetrexed, and pembrolizumab in patients with recurrent/metastatic lung adenocarcinoma.
Authors: Andrew Ip, Martin Gutierrez, Mary E. Warren, David G. Pfister, Owen Brady, Ronglai Shen, Gregory J. Riely
Journal: Journal of Clinical Oncology (2022)

e21045 Background: Randomized clinical trial data support the addition of immune checkpoint inhibitors to standard first-line platinum-doublet in patients with recurrent/metastatic non-small cell lung cancer. In the landmark KN189 Trial in which patients received carboplatin or cisplatin in combination with pemetrexed and pembrolizumab, the updated analysis (Gadgeel et al, JCO 2020) reported a median overall survival of 22 months. To explore the translation of this clinical trial-proven efficacy to clinical effectiveness in routine practice, we sought to explore patient outcomes with the combination of pemetrexed, carboplatin, and pembrolizumab as initial therapy for patients with recurrent or metastatic non-squamous non-small cell lung cancer. Methods: At two large, urban, academic medical centers (Hackensack University Medical Center and Memorial Sloan Kettering Cancer Center), we reviewed patient treatment data to identify all patient all patients with recurrent/metastatic non-squamous non-small cell lung cancer who received carboplatin, pemetrexed, and pembrolizumab as initial therapy for recurrent/metastatic NSCLC from June 2017 to December 2020. Patients with EGFR mutations or ALK gene fusions were excluded. From the medical record, we obtained baseline clinical characteristics, patient treatments and duration, as well as overall survival. Results: We identified 523 patients treated with carboplatin/pemetrexed/pembrolizumab, with 399 events occurring during the observation period. Baseline characteristics: 47% women and median age 66 (Interquartile range 59-72). The median overall survival from start of therapy was 11 months (95% confidence interval 9-12 months). Conclusions: In routine clinical practice, initiation of chemotherapy + immune checkpoint inhibitor as first-line therapy for patients with recurrent/metastatic NSCLC led to shorter median overall survival than reported in clinical trials. To further evaluate this finding, we will explore patient baseline characteristics including performance status, comorbidities, organ function as well as explore outcomes of a historical cohort of patients administered carboplatin and pemetrexed.
Factors associated with default of treatment and follow-up among cancer patients.
Authors: Parmod Kumar, Amit Sehrawat, Sweety Gupta, Deepak sundriyal
Journal: Journal of Clinical Oncology (2022)

e18528 Background: Default during treatment or follow-up is a major area of concern in oncology. Default leads to disease progression, treatment failure, and drug resistance ultimately resulting in increased morbidities and mortality. Default also serves as a mode of confusion and burden to the treating physician who has to re-tailor the treatment. We carried out this study to look for the characteristics and reasons associated with the default during among patients with cancer. Methods: Patients registered with a histologically confirmed diagnosis of solid organ cancer and default during evaluation, treatment, and follow-up were included. Default was defined as skipping a scheduled visit during evaluation by a duration of more than 2 weeks, skipping a scheduled session of chemotherapy by a period of more than the duration between chemo-sessions (week or 2-weeks or 3-weeks), or lost to follow -up (skipped 2 or more scheduled consecutive visits with no further intention of continuing treatment). Information regarding performance status, stage, phase of the treatment, reason for default, educational status of the patient, and demographic profile were noted. Lost to follow-up patients were interviewed telephonically. Results: One hundred seven patients with default were interviewed. Sixty-five percent were males. Thirty-six percent of the patient were of geriatric age-group. Eighty-four percent patients had an ECOG-PS of 0,1 or 2 immediately prior to default. Thirty-three percent of the patient had an early-staged disease. Fifty-four percent of the patients were illiterate. The intent of the treatment was curative in 36 % of the patient. Close to 92% of the patients defaulted during the treatment phase while the rest during evaluation or follow-up. The most common reasons for default were lack of social support (32%), financial distress (22%), difficulty in finding transport (16%), and too sick to come (15%). The lack of social support was evident due to the fear of the loss of daily wages by the family members. The average distance traveled by each patient from home to the cancer center was 131.5 kilometers. Other reasons included poor follow-up counseling by the healthcare staff, demise at home, shifting to alternative treatment (fear of chemo-toxicities), concomitant illness, religious reasons, and general well-being. Thirty-one percent of the patients reported more than one reason for non-compliance. Conclusions: The study reveals illiteracy, lack of social support, and financial distress as major causes of default. Although more than 90% of the patients are covered under PMJAY scheme, which provides free-of-cost treatment, the cost of transportation and the time consumed in commuting to a far-off center adds to the misery. These issues need to be addressed at national levels. Appropriate counselling regarding insight of the disease and adherence to the treatment is desired at the healthcare provider level.
Clinical impact of MAPK pathway alterations in advanced biliary tract cancer (BTC): SCRUM-Japan GOZILA and COLOMATE international collaboration.
Authors: Hideaki Takahashi, Bennett Adam Caughey, Kumiko Umemoto, Michelle Green, Yoshiaki Nakamura, Michael Datto, Makoto Ueno, Daniel Walden, Taito Esaki, Thomas Oliver, Yoshito Komatsu, Nobumasa Mizuno, Eiji Oki, Hiroya Taniguchi, Hideaki Bando, Chigusa Morizane, Takayuki Yoshino, John H Strickler, Masafumi Ikeda, Tanios S. Bekaii-Saab
Journal: Journal of Clinical Oncology (2022)

4086 Background: Abnormalities in the MAPK pathway are potential therapeutic targets in various cancers. However, the clinical impact of alterations in the MAPK pathway in BTC have not been elucidated, especially outside of canonical mutations in KRAS and BRAF. We investigated the clinical outcomes of advanced BTC with MAPK pathway alterations treated with chemotherapy in Japan and the United States. Methods: Patients with advanced BTC who received gemcitabine plus cisplatin as first-line therapy were included from the GOZILA study in Japan and Duke Molecular Registry of Tumors in the US. Genetic abnormalities were detected by Guardant360, a cell-free DNA assay, in Japan and by blood or tissue-based next-generation sequencing (NGS) at Duke University. Two hundred and seven patients with BTC from Japan were included in an exploratory cohort to evaluate the association of MAPK alterations with overall survival (OS) according to MAPK alteration status. One hundred and ten patients with BTC from both Japan and the US harboring oncogenic alterations in the MAPK pathway were included in a biomarker selected cohort to assess the association of specific MAPK alterations with OS. Multivariate analysis was performed using a Cox regression model based on a univariate p-value &lt; 0.2. Results: MAPK pathway-related oncogenic alterations detected in each cohort are shown in the table below. In the exploratory cohort, median OS was shorter for patients with MAPK alterations vs. no MAPK alteration (15.9 m vs. 24.9 m, log-rank p = 0.001). Based on univariate analysis, the following covariates were selected for multivariate analyses: age, prior resection, and MAPK pathway alteration in the exploratory cohort; country, the timing of NGS, distant metastasis, KRAS amplification, and BRAF class 2 mutation in the biomarker selected cohort. In the exploratory cohort, multivariate analysis identified MAPK pathway alterations as an independent predictor of shorter OS with a HR of 1.92 (95% CI = 1.28-2.87, p = 0.001). In the biomarker selected cohort, multivariate analysis identified BRAF class 2 mutations and KRAS amplification as independent predictors of shorter OS with a HR of 16.2 (95% CI = 3.26-80.8, p = 0.001) and 5.97 (95% CI = 1.74-19.3, p = 0.002) respectively. Conclusions: MAPK pathway alterations, especially BRAF class 2 mutation and KRAS amplification, had a significant negative impact on clinical outcomes in BTC receiving first-line chemotherapy. These results are newly confirmed in BTC. [Table: see text]